Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: a retrospective analysis of four years of clinical experience

To the best of our knowledge, this is the largest reported experience of routinely used TDM-guided CI of PIP and customized PIP dosing. Positive effects of CI of β-lactams on patient outcome have been repeatedly reported [17, 19, 22, 34]. An important metanalysis by Roberts et al. [18] with remarkably low heterogeneity (I² = 0 for hospital and ICU mortality) including 632 patients strikingly demonstrated significantly lower 30-day hospital mortality using CI of β-lactams.

We realized the minimum PK-target of ≥ 33 mg/L in 89.9% (n = 435/484) of patients within 24 h of treatment whereas 34.3% (n = 166/484) exactly met the designated PIP target range of 33–64 mg/L. TDM-guided dose adjustments could significantly enhance PK-target attainment (33–64 mg/L) by 81.9% and at the same time effectively reduced the number of patients with potentially harmful concentrations of ≥ 100 mg/L by 85%. Our data do not support previous findings of insufficiently low SCs [9, 35, 36] associated with CI of β-lactams. Underdosing during CI of PIP did rarely occur in the evaluated study cohort (≤ 24 h: 10.1%, n = 49/484; > 24 h: 15.8%, n = 71/449). In contrast to our findings, a recent prospective study of Dhaese et al. [36] found a remarkably high PK-target non-attainment in ICU patients enrolled to receive a CI of PIP (62.9% target non-attainment) or meropenem (25% target non-attainment). A possible explanation for the poor target attainment might be the higher PK-target of 100% fT_>4 ECOFF of PSA (≥ 64–160 mg/L) itself. Although we used a lower PK-target in our study, PIP SCs ≥ 100 mg/L occurred in 30.2% (n = 146/484) of patients within the first 24 h of treatment. We would like to argue that main contributing factors for the divergent target attainment between Dhaese and our study are in fact the different PK-targets and the significantly different study population. Dhaese et al. [36] included younger patients that rarely required vasopressor support which is uncommon in critically ill patients. Our patients are almost 10 years older and the estimated median [IQR] CrCL is more compromised (46.3 mL/h [47.9 mL/h]) as compared to the ICU cohort of Dhaese and coworkers (Pip/Taz 95.4 mL/h [58.3 mL/h]; Mero 117.8 mL/h [68.4 mL/h]). Moreover, APACHE II and SOFA scores were only moderately high and patients with RRT were excluded. Our study cohort comprised 76.6% of patients with sepsis and septic shock including patients with RRT (Table 4). The PK-target (100% fT_>4xECOFF, > 64 ≤ 160 mg/L) defined by Dhaese et al. [36] may be justified in a worst-case-scenario (PSA with MIC 16). EUCAST data show that only 11% of PSA have an MIC of 16. Most of the strains exhibit an MIC of 0.5-8 (https://​mic.​eucast.​org/​Eucast2/​regShow.​jsp?​Id=​6919). Consequently, we defined a lower primary PK-target (100% fT_>2–4xECOFF, 33-64 mg/L) to balance effective bacterial killing and possibly harmful side effects. Our data highlight a U-shaped association of PIP SCs and mortality (Fig. 1). Exposure to higher than defined SCs was associated with significantly higher mortality rates (especially SCs ≥ 100 mg/L), especially in patients with exposure to PIP SCs of 100–160 (hospital mortality 35.5%, ICU mortality 30.4%) and > 160 mg/L (48.4%, 34.8%). We observed the highest survival rate in the patients with target attainment (33–64 mg/L), whereas Dhaese et al. [34] demonstrated a significantly lower survival rate in the group of patients with target attainment. In addition, these patients demonstrated a significantly lower CrCL.

With regard to adverse effects, Imani et al. [37] demonstrated neuro- and nephrotoxicity during bolus application of PIP. Quinton et al. [38] predicted neurotoxicity following continuous application of PIP at around a threshold concentration of 157 mg/L with a sensitivity of 52% which implies that neurotoxicity might well happen above and below 157 mg/L that concentration. Noticeably, patients with neurotoxic symptoms showed a significantly lower eGFR (18 mL/min) as compared to those without neurotoxicity (50 mL/min). The patients with neurotoxicity (n = 23) reached significantly higher PIP SCs (156 mg/L) and demonstrated a relevant reduction of GFR by approximately 45% (33/18 mL/min) within 3 days of antibiotic treatment. In contrast, the rest of the cohort demonstrated an increase of GFR by 13% (44/50 mL/min). On the day of PIP SC measurements, the dose normalized to eGFR (g/24 h/100 mL/min/1.73 m²) was significantly higher in the neurotoxicity group as compared to the rest of the group (48 [35.3–69.7] versus 22 [14.3–54]; p = 0.0111). We do think that this strongly hints to a potentially harmful effect in patients with very high PIP SCs (> 160 mg/L) and supports our finding that PIP SCs considerably higher than 100 and 160 mg/L may in fact be detrimental for kidney function in critically ill patients.

In accordance with previous data [30], we identified age and CrCL as two important factors for PK-target non-attainment in our study cohort: the odds for low PIP SCs significantly increased with high CrCL (< 16 mg/L: OR 1.002 95% CI [1.011–1.034]; 16–32 mg/L: OR 1.017 95% CI [1.013–1.022]; p < 0.0005) while age significantly increased the odds for PIP SCs ≥ 100 mg/L (OR 1.044 95% CI [1.029–1.060]; p < 0.0005). Intensivists need to recognize that exposure to PK-targets impacts treatment success and patient outcome. Higher age and ARC are relevant risk factors for PK-target non-attainment. In that sense, our data are an important contribution to previous studies [35, 39] stating that customized PIP dosing [24] is the only reliable way to enhance PK-target attainment, preventing over- and underdosing and thereby presumably improving patient outcome.

As illustrated in Table 4, impaired renal function (and PIP elimination) may cause high SCs but vice versa, high PIP SCs may readily exacerbate a preexisting renal dysfunction resulting in acute kidney injury with RRT. The potentially nephrotoxic effects of PIP are of special concern when a combination therapy (i.e., vancomycin) is pursued. Recent data clearly illustrate a higher incidence of acute kidney injury in combination therapy and furthermore a distinct effect of piperacillin [40‐42]. Recent data [37] further support the notion that high piperacillin serum concentrations alone may be associated with nephrotoxicity; at least when administered as intermittent bolus application. Patients who developed nephrotoxic signs demonstrated mean PIP trough concentrations > 100 mg/L and those without any signs showed concentrations considerably < 100 mg/L.

As one of only few studies we specifically investigated the effect of RRT on PIP-PK during CI. Consistent with other data [43], we found a considerable reduction of CL_PIP during RRT with markedly higher PIP SCs compared to non-RRT patients. One explanation may be the constant and renal-independent elimination of PIP during. In patients with PIP SCs of ≥ 100 mg/L, we found significantly more patients with acute renal failure requiring RRT. Vice versa, potentially toxic PIP concentrations might as well exacerbate preexisting renal dysfunction and attribute to acute kidney injury [37]. CVVHD is the most commonly used form of RRT in critically ill patients [44, 45] but it is far from being a standardized system. Different modes of operation, variations in flow and the type of hemofilter used may influence CL_PIP and PIP-PK [46‐49].

Although pathophysiologic changes in obese patients [50, 51] may impose dosing problems, our data do not support this notion in the context of CI of PIP. The significantly higher CL_PIP not associated with increased renal drug clearance in patients with a BMI (≥ 40 kg/m²) might hint to increased extra-renal drug clearance, i.e., through the gastrointestinal tract and/or drug deposition in fatty or muscle tissue. A significantly lower target attainment (fT_>4×MIC) in obese patients has been previously demonstrated presumably as a drug-specific effect of piperacillin [52]. Therefore, these data emphasize the rationale for TDM particularly in obese patients in the ICU and the necessity for further trials investigating PIP and β-lactam PK alterations in this subgroup of patients [53‐55].

Our findings underscore the need for definite studies investigating the effects of PK-target attainment along with CI of β-lactams on mortality. The ongoing TARGET study [56], investigating TDM-based dose optimization of piperacillin/tazobactam to improve outcome in patients with sepsis, will particularly address target attainment and CI. The aspect of CI of β-lactams will be re-assessed in the BLING III-study, an ongoing phase 3 multicenter randomized controlled trial investigating continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis [57]. Both studies will also improve our understanding of the PK alterations of β-lactams in critically ill patients.

Our study has several limitations. The data were analyzed retrospectively and drawn from a single center where β-lactams have been routinely and solely been administered as a TDM-guided CI for more than 10 years. In the absence of control groups and possible confounding, mortality data must be interpreted prudentially. Even though we report a large number of routine TDM measurements, correlation with clinical scores [Sepsis-related Organ Failure Assessment Score (SOFA), Simplified Acute Physiology Score (SAPS)] was not possible. Microbiological data and MICs of pathogens were not available for analysis. HPLC was performed to measure PIP concentrations while the combination of PIP and tazobactam (PIP/TAZ) was administered to the patients. Recent evidence, however, suggests that the PK alterations of both PIP and TAZ are almost equal in healthy adults [58] and critically ill patients [59, 60]. β-lactamase inhibition with tazobactam occurs rapidly, within 20–30 min [58] and additionally, piperacillin inhibits tubular excretion of tazobactam [61].